The Pediatric Cardiac Genomics Consortium (PCGC) has been highly successful in studying the genetic basis of congenital heart disease (CHD). We seek to continue our participation in the PCGC's activities as they expand to encompass greater genetic complexity and to understand how genetic factors impact CHD co- morbidities. For SPECIFIC AIM 1, we will use our existing team and robust approach to continue recruitment and phenotyping. The PCGC will study neurodevelopment as it intersects with CHD and genetics. The Mount Sinai team has the requisite infrastructure, both the expertise and phenotyping capability to support whatever studies the consortium selects. For SPECIFIC AIM 2, the Mount Sinai team will leverage a large institutional effort in genomics to engage several genomicists in order to elucidate genetic factors underlying CHD. The PCGC is likely to pursue whole genome sequencing (WGS), work requiring the use of multiple analytic algorithms for structural variation detection and multi-dimensional approaches for non-coding region mutations. We will also provide continued expertise for studies of cardiomyocytes differentiated from patient-derived induced pluripotent stem cells (iPSCs). For SPECIFIC AIM 3, Mount Sinai will contribute to the PCGC's mission of dissecting the role of genetic abnormalities underlying CHD in neurodevelopmental (ND) outcomes. We have access to extensive infrastructure for performing neuropsychological testing. We will provide specific expertise in autism spectrum disorders, which will be quite helpful given the emerging picture of overlap genetically and phenotypically between CHD and autism. Mount Sinai has state-of-the-art facilities for neuroimaging. In addition, our team includes experts in ND outcomes in CHD and neuroimaging. Thus, the Mount Sinai team in its entirety is positioned to contribute to the selection, design, execution and analysis of PCGC projects to explore the impact of CHD genetics on ND outcomes. For the Main Project, we propose to elucidate genetic abnormalities underlying conotruncal forms of CHD, particularly tetralogy of Fallot (TOF) using WGS of trios with affected probands and RNA-seq from cardiac tissues discarded during open-heart surgery, to elucidate epigenetic abnormalities driving CHD using microarray-based DNA methylation assays, and to perform functional genomic assays using patient-derived iPSCs and isogenic controls obtained using gene editing. For the Neurodevelopment Project, we propose to compare neurodevelopmental outcomes in non-syndromic children with TOF with and without causal mutations, based on WGS from the Main Project, hypothesizing that those with mutations will perform worse. We will test children aged 8-to-10 years using a comprehensive neuropsychological assessment battery. To test the hypothesis that structural brain changes and myelination abnormalities are more prevalent among children with TOF and pathogenic genetic findings than among those without genetic abnormalities, we will seek to identify biomarkers using multimodal brain magnetic resonance imaging, including diffusion tensor imaging.